Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:49])[CH2:10][N:11]([C:18](=[O:48])[C@H:19]([CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:47])[NH2:46])[N:20]([N+:38]([O-])=O)[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:25]=1)(=[O:23])=[O:22])[CH2:12][CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1)C1C=CC=CC=1.C(O)(=O)C.O.[H][H]>C(O)C.[Pd]>[N:20]#[N:38].[CH:32]1([C:26]2[CH:25]=[C:24]([S:21]([NH:20][C@H:19]([C:18]([N:11]([CH2:12][CH:13]3[O:17][CH2:16][CH2:15][CH2:14]3)[CH2:10][C:9]([OH:49])=[O:8])=[O:48])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:46])[NH2:47])(=[O:23])=[O:22])[CH:29]=[CH:28][C:27]=2[O:30][CH3:31])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N([C@@H](CCCNC(=N)N)C(=O)N(CC(=O)OCc2ccccc2)CC2CCCO2)[N+](=O)[O-])cc1C1CCCCC1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CC(=O)O)CC2CCCO2)cc1C1CCCCC1
Product: N#N
Yield: 57 %

Procedure:
To a solution of 2.4 g of NG -nitro-N2 -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine benzyl ester in 50 ml of ethanol, 10 ml of acetic acid and 10 ml of water was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 50 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to dryness. The residue was washed several times with dry ethyl ether and chromatographed on 80 ml of Daiaion ® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.1 g (57%) of N2 -(3-cyclohexyl-4-methoxyphenylsulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine as an amorphous solid.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH:9]=[N:10][OH:11])[CH2:2]1.[Cl:12]N1C(=O)CCC1=O>>[OH:11][N:10]=[C:9]([Cl:12])[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:3]21[CH2:2][CH2:1]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=CC1CCCCC12CC2
Product: ON=C(Cl)C1CCCCC12CC2

Procedure:
N-hydroxyspiro[2.5]octane-4-carbimidoyl chloride (I-11J) was prepared by reaction of spiro[2.5]octane-4-carbaldehyde oxime and N-chloro-succinimide following the same protocol as described for I-6B. MS m/z 188.0 (M+1).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N([CH2:12][CH3:13])CC)C>>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:1]1(=[O:6])[O:5][CH:2]1[CH2:12][CH3:13]
Reactant: CCN(CC)CC
Agent: C=C(C)C(=O)O
Product: CCC1OC1=O
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml 3N-RB flask fitted with a gas inlet, thermometer, overhead stirrer and a 125 ml pressure equalizing dropping funnel was added 26.5 g triethylamine. The triethylamine was cooled to 5° C. using a water/ice bath. Once the triethylamine was at 5° C. the methacrylic acid was added dropwise over a 20-25 min period. The mixture exothermed ˜10 C. After the addition was complete the water/ice bath was removed. While the solution was stirring (20 min) the dropping funnel was removed and replaced with a clean 125 ml pressure equalizing dropping funnel. The bromolactone (41.25 g)/THF (62.5 ml) was added dropwise over a 30 min. The mixture warmed from ˜18° C. to ˜30° C. with a precipitate forming. The reaction was heated to 55° C. and held at 55° C. for 16 hrs using an oil bath/hot plate. After heating for 16 hrs the mixture was cooled to 20° C. using a water/ice bath. The solid (44.5 g) was removed by vacuum filtration. The filtrates were reduced under partial pressure at 33-34° C. The resulting dark amber/brown oil was diluted with 90 g of methylene chloride. This solution was slowly poured onto a plug of silica gel (180 g, Baker 40 um flash chromatography packing) which had been pre-conditioned with methylene chloride. The crude mixture was allowed to pass into the silica gel plug by gravity. Once the crude mixture had passed the surface of the silica gel plug a fresh portion of methylene chloride was slowly poured onto the plug. The methylene chloride was pulled through the silica gel plug using reduced pressure. Once the methylene chloride had passed the surface of the silica gel plug the vacuum was removed then the next portion of methylene chloride was slowly poured onto the plug. This procedure was followed until all the product was extracted. The total filtrate was 850 ml. [The product was detected by spotting an aliquot on a TLC plate then illuminating with short UV.] To the orange filtrate was added 36 g of activated charcoal. The mixture was stirred for 1.5 hrs then filtered through a Celite plug (pre-conditioned with methylene chloride). The charcoal/Celite was washed with (2×100 ml, 1×50 ml methylene chloride). The filtrate was then washed with 2×200 ml D.I. water. The layers were separated and the organic layer was dried over 100 g of sodium sulfate. The mixture was stirred for 15-30 min. The sodium sulfate was removed and washed with 2×50 ml methylene chloride. The pale yellow filtrate (1.2 L) was stripped under reduced pressure at 33-34° C. leaving 36.4 g of a pale orange oil, Yield 85.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ccc(-c2ccccc2)c2c1C(=O)NC2
Yield: 88.8 %

Procedure:
In a similar manner to Step 2 of Example 1, 7-amino-4-bromoisoindolinone (250 mg, 1.10 mmol) was dissolved in acetonitrile (15 mL), and the solution was treated with phenylboronic acid (402 mg, 3.30 mmol), palladium acetate (20 mg, 0.088 mmol), tri(o-tolyl)phosphine (53.6 mg, 0.176 mmol) and triethylamine (1.53 mL, 11.0 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=15/1, chloroform/acetonitrile=6/1) to obtain 7-amino-4-phenylisoindolinone (219 mg, yield 89%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)[N:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+:30]1C=CC=CC=1.C(OCC)C>ClCCl>[NH2:30][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(CO)cc2)n1
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(C=O)cc2)n1
Reaction time: 6 h
Yield: 6.7 %

Procedure:
To a suspension of the title compound of Example 41 (375 mg, 1.1 mmol) in dichloromethane (100 ml) was added pyridinium chlorochromate (810 mg, 2.7 mmol) and crushed molecular sieves (1.25 g, 3A). After stirring for 6 hours, diethyl ether (150 ml) was added and the mixture was filtered through a pad of silica gel under suction. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3 followed by 1:2 followed by 1:1) to provide the title compound (25 mg, 7% yield). 1H NMR (DMSO-d6) 10.10 (s, 1H), 9.86 (s, 1H), 8.07 (d, J=8.6 Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 7.79 (s, 1H), 7.43 (m, 2H), 7.34 (m, 2H), 2.53 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([S:11]([NH:22][C:20]3[N:19]([C:23]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:24]=4[CH:25]=[CH:26][CH:27]=[N:28]5)[N:18]=[C:17]([CH3:16])[CH:21]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Reactant: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc21
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc3c(c2)CCC3(C)C)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 30 %

Procedure:
A mixture of 1,1-dimethylindan-5-sulfonyl chloride (0.030 g, 0.13 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.028 g, 0.12 mmol) in pyridine (0.12 mL) was heated at 80° C. for 1 h with stirring. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting crude residue was purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes), followed by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.036 mmol, 28%). 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.90 (d, J=3.2 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.57 (d, J=9.2 Hz, 1H), 7.46 (dd, J=4.0, 8.4 Hz, 1H), 7.30-7.26 (m, 2H), 7.18 (s, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.05 (s, 1H), 2.71 (d, J=7.6 Hz, 2H), 2.20 (s, 3H), 1.84 (d, J=7.2 Hz, 2H), 1.18 (s, 6H); MS: (ES) m/z calculated for C24H25N4O2S [M+H]+ 433.2. found 433.1.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][N:11]([CH2:12][CH3:13])[C:4]=2[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)Cl.CO>[CH2:12]([N:11]1[C:4]2[CH:3]=[C:2]([N:24]3[CH2:23][CH2:22][N:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[F:14])[CH2:26][CH2:25]3)[NH:7][C:6](=[O:8])[C:5]=2[CH:9]=[CH:10]1)[CH3:13]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCn1ccc2c(=O)[nH]c(Cl)cc21
Solvent: CO
Solvent: ClCCl
Product: CCn1ccc2c(=O)[nH]c(N3CCN(c4ccccc4F)CC3)cc21
Temperature: 140 °C
Yield: 65.3 %

Procedure:
A mixture of 6-chloro-1-ethyl-1,5-dihydro-pyrrolo[3,2-c]pyridine-4-one (Intermediate G) (16 mg, 0.081 mmol) and 1-(2-fluorophenyl)piperazine (160 mg, 0.888 mmol) was heated at 140° C. in a sealed tube for 5 h. Flash chromatography (20/1 methylene chloride/methanol) afforded 1-ethyl-6-[4-(2-fluoro-phenyl)-piperazin-1-yl]-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one (18 mg, 65%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.28 Hz, 3H) 3.1 (d, J=4.77 Hz, 4H) 3.2 (d, J=4.77 Hz, 4H) 4.0 (q, J=7.19 Hz, 2H) 5.8 (s, 1H) 6.3 (d, J=3.01 Hz, 1H) 6.9 (d, J=3.01 Hz, 1H) 7.1-7.2 (m, 3H) 10.6 (s, 1H). LC-MS calcd. for C19H22FN4O [(M+H)+] 341, obsd. 341.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]1([NH:27][OH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[OH:28])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: ONc1ccccc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)N(O)c1ccccc1
Yield: 26.4 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and N-phenylhydroxylamine (80 mg, 0.73 mmol) to give 50 mg of the title compound (26%) after silica gel column chromatography with 2% acetic acid/ethyl acetate: mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.04 (s, 1H), 10.01 (s, 1H), 7.56 (d, 2H, J=7.9 Hz), 7.30 (t, 2H, J=7.9 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 7.05 (t, 1H, J=7.4 Hz), 5.17~5.26 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.58~2.62 (m, 2H), 2.09 (dm, 1H, J=13.5 Hz), 1.81~1.95 (m, 1H).
Reaction SMILES: C1(CS(O[CH2:12][CH2:13][C@H:14]([NH:16][S:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH3:15])(=O)=O)C=CC=CC=1.[Cl-:27].[Na+].CN(C)C=O>CCOC(C)=O>[Cl:27][CH2:12][CH2:13][C@H:14]([NH:16][S:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:18])[CH3:15]
Reactant: [Cl-]
Reactant: C[C@H](CCOS(=O)(=O)Cc1ccccc1)NS(=O)(=O)Cc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](CCCl)NS(=O)(=O)Cc1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To the crude (R)-3-(phenylmethylsulfonamido)butyl phenylmethanesulfonate (23.6 mmol) was added sodium chloride (984 mg, 16.8 mmol) and dimethylformamide (37 mL) and the reaction was stirred at 80° C. for 16 hours. The reaction was then diluted with EtOAc, washed with water (×2) and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-50% Acetone in Heptane, 216 nM) to give (R)—N-(4-chlorobutan-2-yl)-1-phenylmethanesulfonamide (1.71 g, 6.53 mmol, 58% yield over 2 steps). LCMS (ESI), m/z, 261 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:13]1([NH2:20])[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.C(N(CC)CC)C.O>CN(C)C=O>[CH2:11]([C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:19][CH:16]3[CH2:17][CH2:18][CH:13]([NH2:20])[CH2:14][CH2:15]3)[C:3]=2[CH:10]=1)[CH3:12]
Reactant: CCc1cc2c(Cl)ncnc2s1
Reactant: NC1CCC(N)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc2c(NC3CCC(N)CC3)ncnc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
Into a 50-mL round-bottom flask, was placed 4-chloro-6-ethylthieno[2,3-d]pyrimidine (200 mg, 1.01 mmol, 1.00 equiv), cyclohexane-1,4-diamine (600 mg, 5.25 mmol, 5.22 equiv) in anhydrous N,N-dimethylformamide (5 mL) at room temperature. Then triethylamine (300 mg, 2.96 mmol, 2.95 equiv) was added via syringe and the resulting solution was stirred overnight at ambient temperature. After completion of the reaction, the resulting solution was diluted H2O, extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This desired 1-N-[6-ethylthieno[2,3-d]pyrimidin-4-yl]cyclohexane-1,4-diamine (0.3 g, crude) was obtained as a off-white solid which was used for next step without further purification.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:22]=[CH:21][C:13]([CH2:14]P(=O)(OC)OC)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O>>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1/[CH:26]=[CH:14]/[C:13]1[CH:21]=[CH:22][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: COP(=O)(Cc1ccc(S(=O)(=O)c2ccccc2)cc1)OC
Reactant: O=Cc1ccccc1F
Product: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccccc2F)cc1

Procedure:
The title compound was prepared from dimethyl [4-(phenylsulfonyl)benzyl]phosphonate (Step 2) and 2-fluorobenzaldehyde according to the method of Example 46 Step 5. δH (500 MHz, CDCl3): 7.97–7.92 (4H, m), 7.63–7.55 (4H, m), 7.52–7.49 (2H, m), 7.35 (1H, d, J=16.5 Hz), 7.30–7.25 (1H, m), 7.18–7.14 (2H, m), 7.10–7.06 (1H, m).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd]>[CH3:19][C:17]1[N:18]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[O:15][C:16]=1[CH3:20]
Reactant: [H][H]
Reactant: Cc1nc(C2CCN(Cc3ccccc3)CC2)oc1C
Agent: [Pd]
Product: Cc1nc(C2CCNCC2)oc1C
Yield: 111.5 %

Procedure:
1.48 g 1-benzyl-4-(4,5-dimethyl-oxazol-2-yl)-piperidine were stirred at RT for 28 h under 50 psi hydrogen atmosphere and 150 mg palladium charcoal. The mixture was filtered and evaporated to give 1.1 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[OH-:19].[Na+]>O.C(Cl)(=O)C1C=CC=CC=1>[C:4]([O:1][C:2]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:5])(=[O:19])[C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:2]=1
Reactant: CCc1ccc(O)c(C(=O)c2ccc(Cl)cc2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: CCc1ccc(OC(=O)c2ccccc2)c(C(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Hydroxy-5-ethyl-4'-chlorobenzophenone (5 g, 0.019 mole) was stirred vigorously in a solution of NaOH (7.5 g, 0.187 mole) in water (75 ml) and benzoyl chloride was added dropwise over 5 minutes. The temperature rose to around 50° C. The mixture was stirred for 1.5 hours at room temperature and was then extracted with ether, the ether washed with saturated NaCl solution, dried (Na2SO4), filtered and evaporated to leave the product, which was recrystallised from n-hexane to give white crystals of the desired product, m.p. 79°-81° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:14]=2)[C:9]([C:25]2[N:30]=[C:29]([O:31][C@@H:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)[CH:28]=[N:27][CH:26]=2)=[N:8]1.[Cl:45][C:46]1[N:51]=[C:50](Cl)[CH:49]=[CH:48][N:47]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:45][C:46]1[N:51]=[C:50]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:8]=[C:9]3[C:25]2[N:30]=[C:29]([O:31][C@@H:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:33]3)[CH:28]=[N:27][CH:26]=2)[CH:49]=[CH:48][N:47]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(B5OC(C)(C)C(C)(C)O5)cc34)n2)C1
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5ccnc(Cl)n5)cc34)n2)C1
Temperature: 100 °C
Yield: 85.9 %

Procedure:
A glass microwave reaction vessel was charged with (3R)-tert-butyl 3-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (600 mg, 0.99 mmol), 2,4-dichloropyrimidine (192 mg, 1.29 mmol, Fluka) and Pd(PPh3)4 (57 mg, 0.050 mmol). The tube was sealed and evacuated under vacuum and back-filled with N2 three times. 2 M Na2CO3 (2.48 mL, 4.95 mmol) and dioxane (5 mL) were added. The reaction was stirred and heated in at 100° C. for 3 h. After cooling to RT, the organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-60% EtOAc in hexanes, to provide (3R)-tert-butyl 3-(6-(5-(2-chloropyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (505 mg, 0.85 mmol, 86% yield) as a pale yellow solid. MS (ESI, pos. ion) m/z: 592.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:22]([O:26][C:27]([NH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]1[NH2:36])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27]([NH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]1[NH:36][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=[C:2]([Cl:1])[N:11]=1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2nc(Cl)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
A solution of 710 mg of 2,4-dichloro-6-methoxyquinazoline in 20 mL of methylene chloride was combined with 471 mg of triethylamine and 750 mg of (1S,2R)-2-tert-butoxycarbonylaminocyclohexylamine, and stirred at room temperature for 48 hours. After concentrating, the mixture was combined with water, extracted with methylene chloride, and dried. After solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol 20:1) to obtain 1.20 g of the desirable compound.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Br:25][C:26]1[CH:32]=[C:31]([O:33][C:34]([F:37])([F:36])[F:35])[CH:30]=[CH:29][C:27]=1[NH2:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:25][C:26]1[CH:32]=[C:31]([O:33][C:34]([F:36])([F:37])[F:35])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2ccc(OC(F)(F)F)cc2Br)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 130 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 3.00 g, 8.08 mmol), 2-bromo-4-(trifluoromethoxy)aniline (2.44 mL, 16.16 mmol), p-toluenesulfonic acid monohydrate (1.64 g, 8.65 mmol) and xylene (7.0 mL) was stirred at 130° C. for 12 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give the title compound as a pale red oil (1.38 g, 2.34 mmol, 29%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:13]=[CH:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:13]=[CH:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: COC(=O)c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cn(-c2cccc([N+](=O)[O-])c2)cn1
Temperature: 120 °C
Yield: 58 %

Procedure:
A mixture of 3-fluoronitrobenzene (1.78 ml; 16.7 mmol), methyl imidazole-4-carboxylate and potassium carbonate (2.3 g; 16.7 mmol) in 10 ml NMP was heated to 120° C. in a nitrogen atmosphere overnight. The cooled mixture was poured into water (100 ml), the precipitate was filtered off, washed with water and dried to yield 6c (2.38 g; 58%).